纵向血压与协调认知功能指标的全基因组多效性分析

Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures.

作者信息

Kang Moonil, Ang Ting Fang Alvin, Devine Sherral A, Sherva Richard, Mukherjee Shubhabrata, Trittschuh Emily H, Scollard Phoebe, Lee Michael, Choi Seo-Eun, Klinedinst Brandon, Nakano Connie, Dumitrescu Logan C, Hohman Timothy J, Cuccaro Michael L, Saykin Andrew J, Kukull Walter A, Bennett David A, Wang Li-San, Mayeux Richard P, Haines Jonathan L, Pericak-Vance Margaret A, Schellenberg Gerard D, Crane Paul K, Au Rhoda, Lunetta Kathryn L, Mez Jesse, Farrer Lindsay A

机构信息

Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.

出版信息

Alzheimers Dement. 2025 Sep;21(9):e70681. doi: 10.1002/alz.70681.

DOI:10.1002/alz.70681

PMID:40951946

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12434708/

Abstract

INTRODUCTION

Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).

METHODS

We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.

RESULTS

Genome-wide significant pleiotropy for BP and cognitive performance with JPH2, GATA3, PAX2, LOC105371656, and SUFU in the total sample; RTN4, ULK2, SORBS2, and LOC100128993 in prospective cohorts; and ADAMTS3 and LINC02946 in clinic-based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment.

DISCUSSION

Our results provide insight into mechanisms underlying hypertension and AD.

HIGHLIGHTS

Genome-wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: JPH2, GATA3, PAX2, LOC105371656, SUFU in the total sample; RTN4, ULK2, SORBS2, LOC100128993 in prospective cohorts; and ADAMTS3, LINC02946 in clinic-based cohorts. SUFU, RTN4, SORBS2, ADAMTS3, and GATA3 affected cognition directly rather than through BP. ACTR1A, HIF1AN, ADAMTS3, RTN4, SORBS2, and SUFU at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.

摘要

引言

识别血压（BP）与认知能力指标之间的多效性可能表明高血压与阿尔茨海默病（AD）之间的机制联系。

方法

我们使用来自25726名临床和前瞻性队列参与者的116075份检查数据，对收缩压、舒张压、脉搏压和平均动脉压与记忆、执行功能和语言得分的配对指标进行了全基因组多效性关联研究（GWAS）。通过贝叶斯共定位和来自有或无临床症状的病理确诊AD病例的脑组织中的差异基因表达，对显著发现进行了评估。

结果

在总样本中，JPH2、GATA3、PAX2、LOC105371656和SUFU与血压和认知能力存在全基因组显著的多效性；在前瞻性队列中，RTN4、ULK2、SORBS²和LOC100128993存在多效性；在临床队列中，ADAMTS3和LINC02946存在多效性。六个多效性位点直接影响认知，并且六个基因在有或无生前认知障碍的病理确诊AD病例之间存在差异表达。

讨论

我们的结果为高血压和AD的潜在机制提供了见解。

要点

在血压（BP）和认知能力指标中识别出全基因组显著的多效性，涉及11个新位点：总样本中的JPH2、GATA3、PAX2、LOC105371656、SUFU；前瞻性队列中的RTN4、ULK2、SORBS2、LOC100128993；临床队列中的ADAMTS3、LINC02946。SUFU、RTN4、SORBS2、ADAMTS3和GATA3直接影响认知，而非通过血压。在多效性位点的ACTR1A、HIF1AN、ADAMTS3、RTN4、SORBS2和SUFU在有或无临床症状的对照和病理确诊AD病例之间存在差异表达。